Background/Purpose: The anti-BAFF antibody belimumab is the first biologic drug approved for treatment of mild-moderate SLE. While the efficacy of belimumab for this indication is not questioned, the mechanism for drug efficacy in humans remains to be established. Mouse studies have shown that BAFF regulates the selection of naïve autoreactive B cells, particularly between the transitional T1 and transitional T2 stage, but that not all autoreactive specificities are subject to regulation by BAFF. Whether belimumab regulates the autoreactive B cell repertoire in humans is not yet known. In addition, an acute increase in CD27+ memory B cells has been noted in patients treated with belimumab. Whether this reflects memory B cell expansion or mobilization, or expansion of the CD27+ B1 subset is not known.

Methods: Peripheral cells from 15 SLE patients treated with Belimumab for >3 years were compared to cells from 17 matched SLE patients and 12 healthy donors. Blood was also collected from 7 patients before and 4-8 weeks after initiation of belimumab treatment. Dendritic cell, monocyte, T cell and B cell subsets were analyzed by multi-parameter flow cytometry. Immunoglobulin heavy chain gene libraries were generated from sorted naive B cells using primers from iRepertoire.

Results: As expected, B cell numbers were 85% lower in chronically treated belimumab subjects than in SLE or healthy controls. Although all B cell subsets were depleted by belimumab, there was relative sparing of the class switched memory subset. In 60% of the patients B cell deletion occurred before the transitional stage, presumably in the bone marrow and in the other 40% it occurred between the T1 and T3 stage. Naïve B cell populations were sorted for immunoglobulin repertoire analyses and good quality libraries were obtained from 14/15 subjects; deep sequencing and analysis are in progress. A modest increase in CD27+ B cells that occurred in patients newly starting belimumab was accounted for by an increase in class switched memory cells but not non-class switched memory or B1 cells. There were no significant differences in dendritic cell, monocyte or T cell subsets between the three groups.

 Conclusion: The effects of belimumab on human B cells are more variable than those in mice and deletion often occurs at an earlier stage of B cell development than the peripheral T1 stage. The increase in CD27+ B cells previously observed early after belimumab therapy is due to an increase in class switched memory cells. Pending repertoire analyses will inform us as to whether there is preferential depletion of autoreactive B cells in belimumab treated patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-effect-of-belimumab-on-peripheral-blood-cells-in-patients-with-systemic-lupus-erythematosus/